Coffee, Citrus, and Alcohol: A Review of What We Drink and How it May Affect our Risk for Skin Cancer

Abstract

Climate change and environmental health are closely linked with agriculture and food supply. The environment influences accessibility, quality, and variety of foods and drinks that are available for consumption, which in turn influences population health. A growing area of research is the role of dietary intake of nutrients and how they may influence risk for skin cancer. In recent years, our group has studied dietary nutrients, particularly those found in commonly consumed beverages, such as those containing caffeine, citrus products, and alcohol, in large prospective cohorts to evaluate how their intake may influence risk for skin cancer. Our data suggest that intake of citrus juices, when consumed around once per day or more, or around 5 to 6 times per week, may be associated with increased risk for both keratinocyte carcinomas (KC) and malignant melanoma (MM). With regards to alcohol consumption, we have found that intake of white wine may be associated with increased risk for both KC and MM, while beer and red wine have not shown such associations. Lastly, our work suggests caffeinated beverages, including coffee, tea, and cola, may be associated with decreased risk for basal cell carcinoma (BCC) and MM. While the associations between food intake and skin cancer development are complex, and remain to be further analyzed in future studies, we hope that our summary may help guide individuals to small changes they may make towards potentially reducing their risk for certain skin cancers.

Introduction

Malignant melanoma (MM) and keratinocyte carcinomas (KC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are amongst the most common types of cancers in the US population and worldwide [1]. The rising incidence in KC is hypothesized to be attributable to, in part, increased levels of individual exposure to UV radiation, especially in geographical regions with greater levels of ozone depletion [2,3]. As climate change progresses, it is important to understand the role of environmental health, including effects on agriculture and access to food, and how this may further influence development of skin cancer.

Climate change and environmental health are closely linked with agriculture and food supply. The environment influences availability, quality, and variety of foods and drinks that are available for consumption, which in turn influences population health [4]. While the association between food and drink intake with risk for skin cancer remains poorly understood, several studies have attempted to elucidate links between consumption of dietary substances and incidence of skin disease [5-8]. Herein, we aim to discuss the associations of certain foods, in particular beverages, including caffeinated beverages, citrus drinks, and alcohol, and how their consumption may be associated with risk for skin cancer in certain populations. We also provide commentary on the interplay of consumption of these beverages and climate and environmental health in populations who are at risk for KC and MM.

Methods

This article presents a summary of studies linking food consumption with risk of skin cancer conducted in the Department of Dermatology at the Warren Alpert Medical School and the Department of Epidemiology, both at Brown University, over the past 10 years, to provide an update to the literature and perspective on consumption of citrus, alcohol, and caffeine related drinks.

Literature Review

Citrus and Citrus Juice

Our group has found that consumption of citrus at high levels, in particular citrus juices, to be associated with an increased risk for both KC and MM. It has been thought that high levels of certain components, such as furocoumarins, may play a role in this association.

Keratinocyte Carcinoma: In 2015, Wu et al. [9] published results of a prospective cohort study of over 40,000 men and 60,000 women, demonstrating an association between higher consumption of citrus products and an increased risk of keratinocyte carcinoma. Using consumption of citrus products less than twice a week as a comparison, there was no increase in risk for those who consumed two to four citrus products per week. However, for those who consumed citrus products 5 to 6 times per week, or more than 1.4 times per day, there was an increased risk of developing both BCC and SCC. Consumption of grapefruit (fruit only, but not juice) and orange juice consistently had positive associations with risk of keratinocyte carcinoma. In this study, there was no difference in risk between men and women.

Due to the hypothesis that furocoumarins may play a role in citrus-related increased risk of skin cancer, in a large prospective cohort study of two populations, Sun et al. [10] analyzed furocoumarin intake calculated from food items containing furocoumarins, including orange fruit, regular orange juice, fortified orange juice with calcium or vitamin D, grapefruit, grapefruit juice, raw carrots, cooked carrots, carrot juice, celery, and lemonade, finding an association between higher intake of furocoumarins and an increased risk of BCC. A food composition database of seven common furocoumarins was used to calculate average and energy-adjusted furocoumarin intake. The association with BCC was significant for both women and men. For SCC, an increased risk was found among women, but not among men. A non-significant positive association was also found with MM.

In another prospective cohort study of nearly 50,000 post-menopausal non-Hispanic white women, ages 50-79 at enrollment, Sakaki et al. [11] found that one or more servings per day of citrus juice was associated with a greater risk of developing KC. Notably, citrus fruits were not associated with increased risk, only citrus juice. However, it is important to note that oranges, grapefruits, and tangerines were grouped together as citrus fruits in the food frequency questionnaire (FFQ) used in the study, with no ability to disaggregate each fruit’s effect. Thus, individual fruits may be associated with increased risk, but could not be assessed in this study.

In an effort to elucidate whether exposure to UV radiation along with dietary citrus juice intake may influence carcinogenesis, Sakaki et al. [11] also investigated possible effect modification on citrus juice consumption of different levels of regional solar radiation exposure, skin reaction to sun, time spent outdoors, and sunscreen use. Looking between different categories within these subgroups, they found no modification in the already significant effect on risk of KC. Contrary to expectations, exposure to higher regional solar radiation of 375-500 Langleys, as compared to 300-350 Langleys, modified the effect of citrus juice consumption to being non-significant, suggesting that when exposed to higher levels of UV radiation, citrus juice consumption did not have an increased risk of skin cancer. While this suggests against the hypothesis that furocoumarins in the skin as a result of citrus juice consumption promote carcinogenesis on exposure to UV radiation, other studies have nonetheless shown increased incidence of melanoma and non-melanoma skin cancer (NMSC) among those who consume high levels of citrus and spend more time outdoors in the summer, and those with skin types that burn more quickly [12].

Malignant Melanoma: As for the results seen for KC, looking at large cohorts of men and women over the course of 24 to 26 years, Wu et al. (2015) [13] found that consumption of citrus products increased risk of cutaneous MM. Compared to those consuming citrus twice per week, risk was increased for those consuming it 5 to 6 times per week, and for those who consumed it more than 1.5 times per day. These associations were consistent between women and men, and were generally independent of age, lifestyle, and dietary confounders, as well as known melanoma risk factors. A synergistic effect of sun exposure and citrus products consumption was proposed by a stronger effect of citrus products on patients who had higher sunburn susceptibility and higher UV radiation exposure. It was also found that consumption of citrus products was more strongly associated with occurrence of MM on areas of the body that may receive higher levels of continuous UV exposure, such as the head, neck, and extremities. Grapefruit consumption showed the most apparent association when comparing individual citrus products (vs grapefruit juice, oranges, orange juice).

Furthermore, Melough et al. (2020) investigated the association between citrus consumption and melanoma risk in greater than 50,000 post-menopausal Caucasian women in the Women’s Health Initiative [12]. While total citrus consumption was not associated with incidence of MM, those who consumed the highest levels of citrus juice (greater than 1 serving a day), as compared with those who consumed the lowest levels (less than 1 serving a week), had a significantly greater risk of MM. This was not the case, however, with citrus fruits or non-citrus containing juices. Additionally, higher levels of citrus juice consumption were associated with higher risk for MM for those women who spent greater than 30 minutes per day outside during the summer in adulthood, highlighting further the possibility that increased skin cancer risk with citrus juice consumption is possibly mechanistically linked to UV exposure.

Putative Pathomechanism: It is postulated that this associations of increased risk of skin cancers may be a result of high levels of furocoumarins found in citrus products. Furocoumarins are known photosensitizers and are considered to be carcinogenic when combined with UV exposure [14]. 8-methylpsoralen (8-MOP) and 4,5′8-trimethylpsoralen (TMP) are furocoumarins which are used to photosensitize during psoralen and UV radiation (PUVA) treatments, which are known to increase risk for skin cancer, in particular SCC. Furocoumarins are found in many plant-based foods, and upon consumption can be quickly re-distributed to many tissues, including the skin [15]. It is hypothesized that when skin is exposed to UV radiation, furocoumarins re-distributed to the skin may be photoactivated, and subsequently cause DNA intercalation, promote mutations, and interfere with DNA transcription within keratinocytes and melanocytes [15].

Furthermore, we hypothesize that the consumption of high quantities of citrus juices may be more strongly associated with development of skin cancers as opposed to citrus fruits themselves, due to higher furocoumarin content in fruit peels which are often incorporated into the juice through the juicing process. In several studies, grapefruit showed an association with increased skin cancer risk, while oranges did not. While both contain furocoumarins, there are higher levels in grapefruit, which may explain this finding [16,17].

Alcohol

Alcohol consumption has been associated with occurrence of numerous malignancies including breast cancer, prostate cancer, and cancers of the GI tract. Furthermore, alcohol consumption has been associated with increased risk for severe sunburn. Our group has shown increased risk of BCC and MM with alcohol consumption. In particular, white wine and liquor have been associated with BCC risk, and white wine has been associated with MM risk.

Keratinocyte Carcinoma: Looking at three large cohorts of men and women, Wu et al., (2015) [18] found that alcohol consumption was associated with increased risk of developing BCC across all levels of alcohol measured, suggesting an effect independent of amount of alcohol consumed. This relationship was consistent over different categories of sun exposure and across sex. Among alcoholic beverages, white wine and liquor consumption in particular were associated with increased risk, while beer and red wine were not. Alcohol consumption around ages 18-22 years old, particularly in women, was also a risk factor.

Looking across three large cohorts of White patients in the US (Nurses’ Health Study (NHS), Nurses’ Health Study II (NHSII), Health Professionals’ Follow-up Study (NPFS)), Siiskonen et al. [19] found that alcohol intake was associated with SCC in a dose-response relationship, and specifically white wine intake greater than 5 times per week was associated with an elevated risk. Women appeared to have higher risk than men within the same alcohol intake levels.

Malignant Melanoma: Rivera et al. [20] found that alcohol consumption was also associated with increased risk of invasive melanoma. Disaggregated analysis by alcoholic beverage revealed white wine to be significantly associated with this increased risk when controlling for consumption of beer, red wine, as well as liquor. For the heaviest drinkers in the study (ie, >20g of alcohol per day) the strongest association was for increased risk of melanoma in the trunk, a non-UV-exposed area.

Putative Pathomechanism: While it is known that ethanol is not carcinogenic, it is hypothesized that metabolites of alcohol beverages, such as acetaldehyde, may serve as photosensitizers, thereby increasing the risk of sunburn and UV-induced carcinogenesis [21]. Acetaldehyde also produces reactive oxygen species on exposure to UV radiation, which would have further potential to induce DNA damage [22]. Alcohol also causes immunosuppression, which may influence immune-related skin cancer surveillance [23]. Several of our studies have found white wine to be associated with increased risk as compared with other types of alcohol. White wine contains fewer antioxidant phenolic compounds than red wine, and also contains higher concentrations of acetaldehyde and sulfites, which is thought to contribute to the increased risk [24-26]. While no association between consumption of these compounds has been proven, it is possible that these effects may play a role.

Caffeine

While citrus juice and alcohol have been associated with increased risk of skin cancer, coffee drinkers may be in luck. Caffeinated beverages, including coffee, tea, and cola, have been associated with decreased risk for BCC, and may be associated with decreased risk for MM.

Keratinocyte Carcinoma: Song et al. [27] found that caffeine intake was inversely associated with BCC. As compared with women who drank less than 1 cup of coffee per day, those that drank 3 or more cups had a lower risk of BCC. Other beverages which contain caffeine (tea, cola, chocolate) also exhibited this relationship with BCC, whereas decaffeinated beverages did not. In this study, there was no association found for SCC or MM.

Malignant Melanoma: Wu et al. (2015) [28] have also showed an association between caffeine intake and decreased risk in development of cutaneous MM, which was significant for women but not for men, although the trends were negative association for both. There was a significant association with melanomas occurring on body sites with higher continuous sun exposure (head, neck, extremities), when compared to areas with lower continuous sun exposure such as the trunk, shoulder, back, hip, abdomen, chest.

Putative Pathomechanism: It has been hypothesized that beverages high in caffeine, including coffee and black tea, are also high in polyphenol antioxidants. Mouse studies and in vitro studies on human cells have suggested that caffeine can promote apoptosis of UV-damaged keratinocytes and thereby potentially reduce development of subsequent skin cancer [29,30].

Furthermore, caffeine has been suggested to disrupt the ATR/Chk1 pathway or inhibit UV-induced phosphorylation of Chk1 [30,31]. In vitro studies on human cells showed that caffeine augmented UV-induced apoptosis of keratinocytes through inhibition of the ATR/Chk1 pathway [29]. Thus, it is hypothesized that caffeine may facilitate apoptosis of cells exposed to UV radiation and reduce UV-induced KC.

Conclusion

With rising incidences of skin cancers including KC and MM worldwide, it is important to evaluate factors that may influence skin cancer occurrence. While exposure to UV radiation, lighter Fitzpatrick skin type, and history of blistering sun burns are individual level factors that have been studied, the complex interplay between environmental health and risk for skin cancer remains to be fully explored.

A growing area of research is the role of dietary intake of nutrients and how they may influence risk for skin cancer. In recent years, our group has studied dietary nutrients, particularly those found in commonly consumed beverages, in large prospective cohorts to evaluate how their intake may influence risk for skin cancer (Figure 1).

Figure 1.

Summary of recommendations regarding beverage consumption and risk of skin cancers. Created with Biorender.com.

Our data suggest that intake of certain citrus products may be associated with increased risks of certain skin cancers. Citrus juices, when consumed around once per day or more, or around 5 to 6 times per week, may be associated with increased risk for both KC and MM. While in some studies intake of citrus fruits, including grapefruits, were not found to result in increased risk, in one study grapefruits did confer increased risk. Thus, we posit that intake of most citrus fruits may not have significant risk, while the role of grapefruit remains to be further studied. We hypothesize that this may be a result of furocoumarins. There may be higher levels of furocoumarins in citrus juices as compared with citrus fruits because citrus juices often incorporate components of the peel, which is high in furocoumarin content. It is thought that the furocoumarins may act as photosensitizers and promote carcinogenesis following UV exposure, however this putative mechanism remains to be fully elucidated and proven.

With regards to alcohol consumption, we have found that intake of white wine may be associated with increased risk for both KC and MM. Beer and red wine have not shown such associations. Liquor was associated with increased risk in one study, but not in another, thus this association remains to be further understood. As for citrus fruits, it is thought that the increased risk is a result of compounds that serve as photosensitizers, in this case metabolites such as acetaldehyde. White wine is thought to have lower concentrations of antioxidant phenolic compounds and higher concentrations of acetaldehyde and sulfites, possibly resulting in increased risk.

Lastly, our work suggests caffeinated beverages, including coffee, tea, and cola, may be associated with decreased risk for BCC and MM. One study found decreased risk for BCC, but not for MM, and another found decreased risk for MM. Neither study found increased risk for any type of skin cancer with increased caffeine intake. While the trends were significant for both men and women, particularly women who drank more than three cups per day of coffee had decreased risk of BCC. Our work also suggests that increased caffeine intake is associated with lowered risk for MM, particularly in women.

While the associations between food intake and skin cancer development are complex and remain to be further analyzed in future studies, we hope that our summary may help guide individuals to small changes they may make towards potentially reducing their risk for certain skin cancers.

Glossary

KC

keratinocyte carcinomas

MM

malignant melanoma

BCC

basal cell carcinoma

SCC

squamous cell carcinoma